This application is a request for funding of the SPORE in Prostate Cancer at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (RHLCCC), the University of Chicago Medicine Comprehensive Cancer Center (UCCCC), and NorthShore University HealthSystems (NS/UC), with contributions from the University of California San Francisco (UCSF), University of Southern California (USC) and University of Pittsburgh. We propose four projects: 1) Impact of germline genetic variants on failure of active surveillance for prostate cancer (Catalona, Witte, Brendler), 2) Glucocorticoid receptor antagonism in castration-resistant prostate cancer (Szmulewitz, Conzen), 3) EphB4 receptor kinase as a target in prostate cancer (Abdulkadir, Stadler), 4) Targeting FOXA1-downstream pathways: a novel therapeutic strategy for castration-resistant prostate cancer (Yu, Kuzel). The four proposed projects refine our ability to detect lethal prostate cancer (Project 1), identify additional biomarkers for disease aggressiveness and response to targeted therapy in personalized medicine (Projects 1-4) and will improve therapy for castrate-resistant prostate cancer (Projects 2-4) in translational cancer research. The Core facilities (Administrative, Advocacy and Leadership Development, Biostatistics/Bioinformatics, Biospecimen Pathology) will support the development of the clinical trials, the analysis of data and the collection of blod and tissue specimens. Under the Administrative Core, SPORE investigators will be closely monitored and will continue to be highly interactive, meeting monthly in addition to holding small group meetings on a regular basis. The SPORE Internal and External Advisory Boards will offer guidance to the SPORE on a regular basis and the SPORE will support an Advocacy Group and both Developmental Research and Career Development Programs. Furthermore, the results obtained from SPORE studies will be made available to all cancer investigators in the RHLCCC, UCCCC and NS/UC through a variety of mechanisms including seminars, symposia, web site, publications etc. Finally, the Administrative Core introduces a Leadership Program that will mentor young investigators in developing their careers and becoming future SPORE cancer research leaders. All together, we anticipate that the results obtained through this SPORE Program will have a significant impact on patients affected by prostate cancer.